This will be a phase I study of carfilzomib in combination with vorinostat in patients with relapsed/refractory B-cell lymphomas. Combination therapy with proteosome inhibitor PR-171 and HDAC inhibitors is highly synergistic in primary DLBCL cells, and both classes of drugs can also synergize powerfully to induce cell death in bortezomib-resistant cells. The purpose of this study is to see if vorinostat can combine with carfilzomib and to safely find the recommended phase II dose.

Study Drugs:

Vorinostat, a class I/II pan-histone deacetylase inhibitor (HDACI), was the first approved agent og this class on the basis of activity in refractory cutaneous T-cell Lymphoma. Lethal mechanisms include anti-apoptotic protein down-regulation, up-regulation of proapoptotic proteins, induction of ROS, death receptor up-regulation, and disruption of chaperone function and DNA-repair proteins.

Carfilzomib, is a irreversible proteasome inhibitor of the epoxyketone class that exhibits a high level of selectivity for the proteosome. This agent induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis.

Study Drug Administration:

If you are found to be eligible to take part in this study:

• Vorinostat PO twice daily on Days 1, 2, 3, 8, 9, 10, 15, 16 and 17.
• Daily Carfilzomib 30 minutes infusion on Days 1, 2, 8, 9, 15, 16.
• Administer first daily dose of vorinostat prior to carfilzomib on Days 1, 2, 8, 9, 15, 16
• Cycle repeated every 28 days, up to 13 cycles.

Carfilzomib will be given at 20mg/m2 for days 1 and 2 of cycle 1 only, then escalated to the higher dose indicated in the schema on day 8 of cycle 1 and thereafter. Carfilzomib treatment is to be done early in the morning and have a minimum of a 6 hour observation period after the infusion. For patients with good tolerability to carfilzomib during the first cycle, an observation period of 2 hours is recommended. A minimum of 16 hours should separate doses of carfilzomib, so that the day 1 dose may be given in the afternoon and the day 2 dose in morning during cycle 2 and subsequent cycles for patients who tolerate the drug well.

If two out of 6 patients do not tolerate the initial dose of 20 mg/m2 carfilzomib on days 1 & 2 followed by 27 mg/m2 carfilzomib for subsequent doses and 200 mg/day bid vorinostat, the next patient should be dose reduced to 20 mg/m2 carfilzomib and 100 mg/day bid vorinostat.

Study Visits:

• Baseline within 4 weeks of Cycle 1 Day 1.
• CT or physical exam.
• Bone marrow if needed to follow disease status.
• PET recommended but not required. To document complete response (CR), a PET is REQUIRED.
• Optional research tumor biopsy.
• Peripheral blood obtained for PD prior to initiation of treatment and at 48 hours +/- 6 hours after receiving first dose of Carfilzomib , and at Off Study.
• End of Treatment Restaging will take place 6-8 weeks after completion of treatment and will include an assessment by the physician, labs, and a tumor response evaluation.
• After completion of Restaging exams, Follow up exams will take place every 6 months for 2 years and then annually until disease progression or initiation of another treatment.
• An Off Study visit will take place at the time of disease progression or initiation of another treatment, which will include assessment by the physician,a tumor response evaluation, labs, and a final PD sample, by the patient's consent.

Inclusion Criteria:

• Histologically confirmed B-cell lymphomas, excluding CLL (Chronic Lymphocytic Leukemia), that is recurrent or refractory after at least one prior therapy and for which no other potentially curative therapy is available.

• Age ≥ 18 years

• ECOG Performance Status (PS) ≤ 2

• Laboratory parameters

  • if SLL, lymphocyte count < 5,000/µL
  • Absolute neutrophil count ≥ 1000/µL
  • Platelets ≥ 75,000/µL
  • Creatinine ≤ 1.5x upper limit of normal or calculated creatinine clearance > 40mL/min
  • AST, ALT ≤ 2.5 x upper limit of normal (ULN)
  • Bilirubin ≤ 2.0 mg/mL
  • Serum potassium ≥ 3.5 mEq/L and serum magnesium ≥ 1.7 mEq/dL (electrolytes may be corrected with supplementation).
  • PT < 1.5 x ULN and PTT < 1.2 x ULN (unless receiving therapeutic anticoagulation).

• Patient is, in investigator's opinion, willing and able to comply with the protocol requirements and offers written informed consent.

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control ( i.e., oral injectable hormonal methods; barrier methods such as intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence)for the duration of the study.

• Male subject agrees to use an acceptable method for contraception for the duration of study.

Exclusion Criteria:

• History of brain metastasis including leptomeningeal metastasis.
• Chemotherapy of radiotherapy within 3 weeks prior to entering the study.
• Prior histone deacetylase inhibitor as cancer treatment.
• Concurrent treatment with other investigational agents or cancer treatment.
• Unable to take oral medications.
• Active ischemic heart disease or congestive heart failure. If there is suspicion of cardiac disease, left ventricular ejection fraction (LVEF) must be ≥ 45%, otherwise study to evaluate EF is not required.
• Persistent blood pressure (BP) of ≥ 160/95 (three separate readings on different days).
• History of allergic reactions attributed to compounds of similar chemical or biological composition to carfilzomib and vorinostat.
• Known clinical significant infection including infection with human immunodeficiency virus (HIV), or active hepatitis B or C, requiring treatment.
• Serious medical or psychiatric illness likely to interfere with patient participation.
• Pregnant or nursing. Confirmation that a woman is not pregnant must be established by a negative serum pregnancy test result obtained at screening.
• Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• No prior allogeneic stem cell transplant.
• Patients scheduled for any type of stem cell transplant within 4 weeks of treatment.
• Patients who have valproic acid for epilepsy can enroll, provided that they stopped drug at least 30 days prior to enrollment and they will be on a stable, effective dose of an alternative anti-seizure medication.